Bilateral Symmetrical Pallidal Lesions Following Severe Anemia Associated with Gastrointestinal Hemorrhage: Report of Two Cases

□ CASE REPORT □

Takahisa Shibata 1, Masayuki Ueda 1,2, Toshiaki Ban 1 and Yasuo Katayama 2

Abstract

We herein report the cases of two patients with bilateral symmetrical pallidal lesions mimicking hypoxic encephalopathy following severe anemia associated with gastrointestinal hemorrhage despite a lack of carbon monoxide intoxication. Although severe anemia can theoretically result in anemic hypoxia, vulnerable pallidal lesions have rarely been described in anemic patients. Interestingly, both patients shared common conditions associated with atherosclerosis, including heavy smoking, hypertension, type 2 diabetes mellitus and a history of coronary artery bypass grafting for ischemic heart disease. Anemic hypoxia may cause pallidal involvement in atherosclerotic patients with multiple risk factors.

Key words: hypoxic encephalopathy, anemia, gastrointestinal hemorrhage, globus pallidus, atherosclerosis, type 2 diabetes mellitus

(Intern Med 52: 1625-1628, 2013) (DOI: 10.2169/internalmedicine.52.0047)

vere anemia associated with gastrointestinal hemorrhage. Introduction Case Reports The globus pallidus is predominantly affected in patients with hypoxic encephalopathy, while bilateral symmetrical Patient 1 pallidal lesions are typically observed in patients with carbon monoxide (CO) intoxication (1). Hypoxic damage is A 56-year-old heavy smoking man with type 2 diabetes classified into several types. In addition to well-known was admitted to our hospital due to mild dysarthria and dis- hypoxic-ischemic injury occurring after cardiac arrest, hy- orientation that developed on the day of admission. He had poxic hypoxia (a decreased partial pressure of arterial oxy- smoked 20 to 40 cigarettes a day for over 30 years prior to gen), histotoxic hypoxia (impaired oxygen utilization by tis- admission. He complained of epigastralgia and tarry stools sue) and anemic hypoxia (a decreased normal hemoglobin starting five days before admission. He had taken aspirin, ti- level) have been identified (2). CO exerts direct toxicity on clopidine and nitroglycerin since undergoing coronary artery mitochondrial enzyme cytochrome oxidase (histotoxic hy- bypass grafting (CABG) following a myocardial infarction poxia) and exhibits a high ability to bind hemoglobin (ane- at 52 years of age and was also being treated with β- mic hypoxia) (1, 3, 4). Therefore, CO exposure is consid- blockers, diuretics and sulfonylureas for hypertension and ered to be more toxic than simple anemia. Although severe diabetes. His diabetes had been well controlled (HbA1c: anemia theoretically results in anemic hypoxia, vulnerable 5.8% NGSP on admission); however, the casual blood glu- pallidal lesions have rarely been described in anemic pa- cose level on admission was 198 mg/dL. The patient’s ordi- tients. We experienced two patients displaying bilateral sym- nary systolic blood pressure was 160 mmHg, and he exhib- metrical pallidal lesions on magnetic resonance imaging ited relative hypotension (blood pressure: 100/60 mmHg) (MRI) that mimicked hypoxic encephalopathy following se- without tachycardia (heart rate: 72/min). A routine blood ex-

１Department of Internal Medicine, Isumi Medical Center, Japan and ２Department of Neurology, Nippon Medical School, Japan. Received for publication January 4, 2013; Accepted for publication February 19, 2013 Correspondence to Dr. Takahisa Shibata, [email protected]

1625 Intern Med 52: 1625-1628, 2013 DOI: 10.2169/internalmedicine.52.0047

Figure 1. Brain MRI of Patient 1. Brain MRI performed on admission showing high signal inten- sity lesions in the bilateral globus pallidus on DWI images (A) as well as FLAIR images (B). MRA displaying atherosclerotic arteries (C). Follow-up MRI performed four weeks after admission dem- onstrating negative findings on DWI images (D) and bilateral pallidal hyperintensity on FLAIR images (E).

amination revealed that the hemoglobin level was extremely formed four weeks later. The patient completely recovered decreased to 6.2 g/dL from a baseline of 15.0 g/dL. An arte- and was discharged from the hospital without assistance. rial blood gas analysis showed slight hypoxemia (pH: 7.432, Patient 2 PCO2: 36.5 mmHg, PO2: 75.0 mmHg, HCO3: 23.9 mmol/L,

SaO2: 95.8%). An electrocardiogram disclosed inferior pa- A 72-year-old man was admitted to our hospital due to thologic Q waves and an echocardiogram displayed pos- appetite loss and headaches. He also complained of tarry teroinferior akinesis and a low ejection fraction of 41%. stools starting 10 days before admission. He had undergone Brain MRI performed on the day of admission demonstrated open surgery for CABG at 65 years of age due to unstable bilateral pallidal lesions on diffusion-weighted imaging angina. In addition, he had been treated with percutaneous (DWI) and fluid-attenuated inversion recovery (FLAIR) im- coronary intervention at 68 years of age due to recurrent un- aging (Fig. 1A, B). Magnetic resonance angiography (MRA) stable angina attacks. He had smoked approximately 40 displayed atherosclerotic, but not stenotic, large intracranial cigarettes a day for 50 years, but had stopped smoking since arteries (Fig. 1C). A carotid ultrasound examination also re- then. He had taken warfarin, clopidogrel, nitroglycerin, pi- vealed atherosclerotic carotid arteries. There were no causa- tavastatin, calcium channel blocker and diuretics prior to ad- tive episodes of CO intoxication, such as motor vehicle ex- mission. He was also being treated with pioglitazone, met- haust or smoke inhalation, and no history of resuscitation. formin and intensive insulin therapy for type 2 diabetes; Emergent endoscopy revealed a hemorrhagic duodenal ulcer. however, his diabetes was not well controlled (HbA1c: 6.9- The patient was treated with a blood transfusion followed 7.9 NGSP). His casual blood glucose level was 165 mg/dL by iron medication as well as a proton pump inhibitor. His on admission. His blood pressure was controlled in the hemoglobin concentration recovered to 10.0 g/dL within one range of 130-140/60-80 mmHg and was slightly decreased week, and his consciousness level eventually improved in to 113/52 mmHg on admission. His ordinary heart rate association with increases in the hemoglobin level. The pal- ranged from approximately 80 to 90 beats/min and remained lidal lesions exhibited FLAIR hyperintensity; however, no essentially unchanged (72 beats/min) on admission. A labo- DWI abnormalities were observed on follow-up MRI per- ratory examination revealed that the hemoglobin level was

1626 Intern Med 52: 1625-1628, 2013 DOI: 10.2169/internalmedicine.52.0047

Figure 2. Brain MRI of Patient 2. Brain MRI performed on admission displaying high signal in- tensity in the bilateral globus pallidus on DWI images (A) and FLAIR images (B), with atherosclerosis in the left internal carotid artery on MRA (C). Follow-up MRI performed two weeks after admission disclosing no DWI abnormalities (D) with bilateral pallidal FLAIR hyperintensity (E). extremely decreased to 5.6 g/dL from a baseline of 13.0 g/ dL. An arterial blood gas analysis was not conducted; how- Discussion ever, the patient’s SpO2 on room air was 100%. An electrocardiogram disclosed complete right bundle branch block The present patients demonstrated similar manifestations without any ischemic changes. An echocardiogram displayed characterized by bilateral symmetrical pallidal involvement hypokinesis of the anteroseptal and posterior regions; how- following severe hemorrhagic anemia. Various pathologic ever, his ejection fraction was normal (62%). The patient de- conditions that result in oxygen or glucose deprivation can veloped delirium on the day of admission. On day 3, no de- damage the basal ganglia due to the high energy require- lirium was observed, although the patient eventually devel- ments of these regions (3). The globus pallidus, in particu- oped apathy. Brain MRI demonstrated bilateral pallidal le- lar, located in the watershed blood supply area, may be sions on DWI and FLAIR images (Fig. 2A, B). MRA more vulnerable (1). Bilateral pallidal involvement is one of showed atherosclerotic, but not stenotic, large intracranial the radiological characteristics of CO intoxication (1); how- arteries (Fig. 2C). A carotid ultrasound examination also dis- ever, neither patient had a history of episodes of high CO closed atherosclerotic carotid arteries. There were neither exposure. Although the precise mechanisms of the pallidal causative episodes of CO intoxication nor a history of resus- involvement were unclear, several pathogeneses were con- citation. Endoscopic analyses of the upper gastrointestinal sidered. As the arterial oxygen content is calculated as 13.4× and lower total colonic tracts did not show any hemorrhagic Hb×SaO2+0.03×PaO2 (5), severe anemia can lead to anemic lesions despite the patient’s massive tarry stools, suggesting hypoxia, potentially impairing oxygen delivery to tissues, in- that hemorrhagic lesions were in the small intestine. He was cluding the brain. Indeed, the hemoglobin levels were sud- treated with a blood transfusion followed by iron medication denly decreased to less than half of the baseline values in as well as a proton pump inhibitor, and his hemoglobin con- the present patients, indicating abrupt reductions in the arte- centration promptly recovered. On follow-up MRI per- rial oxygen content. The impaired oxygen delivery observed formed two weeks later, no pallidal hyperintensity was ob- under an anemic state is usually compensated for by in- served on DWI, although it remained on FLAIR images. creases in cardiac output (5). However, abrupt decreases in The patient’s apathy lasted during admission; however, his circulating blood volume following gastrointestinal hemor- condition gradually improved. Two months after developing rhage probably interfered with compensation in our patients. apathy, he had almost recovered. Especially in Patient 1, a low ejection fraction associated

1627 Intern Med 52: 1625-1628, 2013 DOI: 10.2169/internalmedicine.52.0047 with myocardial infarction may have disturbed compensa- veloped following severe anemia associated with gastrointes- tion, and β-blocker use may have inhibited tachycardic com- tinal hemorrhage, despite a lack of episodes of CO intoxica- pensation for the patient’s anemic state. In addition, current tion or resuscitation. Hemorrhagic anemia is common in cigarette smoking may have influenced the pallidal damage clinical practice. Therefore, physicians should be aware of observed in Patient 1 due to the elevated carboxyhemoglo- rare, but important, causes of hypoxic brain damage because bin level that occurs in smokers (6). anemic hypoxia, in combination with ischemic hypoxia, can

The relatively low arterial PCO2 level caused by hypoxia- lead to deterioration of the vulnerable globus pallidus. induced hyperventilation observed in Patient 1 may have contributed to further reductions in the cerebral blood flow The authors state that they have no Conflict of Interest (COI). (CBF) due to CBF decreases in response to low arterial

PCO2 levels (7). Moreover, both patients had multiple risk References factors for atherosclerosis, including a history of heavy smoking, hypertension and type 2 diabetes, and exhibited 1. Prockop LD, Chichkova RI. Carbon monoxide intoxication: an up- atherosclerotic large intracranial arteries on MRA. In par- dated review. J Neurol Sci 262: 122-130, 2007. ticular, type 2 diabetic patients reportedly display reduced 2. Singhal AB, Topcuoglu MA, Koroshetz WJ. Diffusion MRI in three types of anoxic encephalopathy. J Neurol Sci 196: 37-40, CBF velocity, increased cerebrovascular resistance and im- 2002. paired CO2 reactivity (8). Therefore, the presence of type 2 3. Ho VB, Fitz CR, Chuang SH, Geyer CA. Bilateral basal ganglia diabetes and atherosclerosis may have contributed to further lesions: pediatric differential considerations. Radiographics 13: cerebral perfusion impairment following gastrointestinal 269-292, 1993. hemorrhage in these patients, resulting in ischemic hypoxia 4. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med 339: 1603-1608, 1998. in addition to anemic hypoxia. 5. Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: There are only two reports describing hypoxic encephalo- hemorrhagic shock. Crit Care 8: 373-381, 2004. pathy occurring under massive hemorrhage in the litera- 6. Wald NJ, Idle M, Boreham J, Bailey A. Carbon monoxide in ture (9, 10). Lou et al. reported a case of delayed hypoxic breath in relation to smoking and carboxyhaemoglobin levels. encephalopathy following gastrointestinal hemorrhage in Thorax 36: 366-369, 1981. 7. Brian JE Jr. Carbon dioxide and the cerebral circulation. Anesthe- which the patient displayed symmetrical involvement of the siology 88: 1365-1386, 1998. bilateral globus pallidus and the substantia nigra (9). Mizu- 8. Novak V, Last D, Alsop DC, et al. Cerebral blood flow velocity tani et al. also described a case of delayed hypoxic encepha- and periventricular white matter hyperintensities in type 2 diabe- lopathy following shock associated with a contusion and tes. Diabetes Care 29: 1529-1534, 2006. laceration of the liver in a traffic accident (10). The previ- 9. Lou M, Jing CH, Selim MH, Caplan LR, Ding MP. Delayed sub- ously reported patients were resuscitated before developing stantia nigra damage and leukoencephalopathy after hypoxic- ischemic injury. J Neurol Sci 277: 147-149, 2009. hypoxic encephalopathy (9, 10); therefore, hypoxic-hypoxia 10. Mizutani T, Shiozawa R, Takemori S, Tsurumaru M, Akiyama H. rather than anemic hypoxia may have been the primary Delayed post-anoxic encephalopathy without relation to carbon mechanism for their ischemic brain injuries. The present pa- monoxide poisoning. Intern Med 32: 430-433, 1993. tients are unique because their bilateral pallidal lesions de-

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